Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer

TRPM8 ion channels, the primary cold sensors in humans, are activated by innocuous cooling (<28 °C) and cooling compounds (menthol, icilin) and are implicated in sensing unpleasant cold stimuli as well as in mammalian thermoregulation. Overexpression of these thermoregulators in prostate cancer and in other life-threatening tumors, along with their contribution to an increasing number of pathological conditions, opens a plethora of medicinal chemistry opportunities to develop receptor modulators. This Perspective seeks to describe current known modulators for this ion channel because both agonists and antagonists may be useful for the treatment of most TRPM8-mediated pathologies. We primarily focus on SAR data for the different families of compounds and the pharmacological properties of the most promising ligands. Furthermore, we also address the knowledge about the channel structure, although still in its infancy, and the role of the TRPM8 protein signalplex to channel function and dysfunction. We finally outline the potential future prospects of the challenging TRPM8 drug discovery fieldWe thank Gregorio Fernández-Ballester for the figure of the TRPM8 homology model. Funding from the Ministry of Economy and Competitiveness (BFU 2012-39092-C02; SAF2015-66275-C2-R) and the Generalitat Valenciana (PROMETEO II/2014/011).Peer reviewe

Conformationally restricted PACAP27 analogues incorporating type II/II′ IBTM β-Turn mimetics. Synthesis, NMR structure determination, and binding affinity

To probe the importance of a proposed β-turn within residues S9-R12 of PACAP for recognition by VIP/PACAP receptors, compounds 1 and 2, two conformationally restricted analogues of PACAP27 incorporating respectively (S)- or (R)-IBTM as type II or II′ β-turn dipeptide mimetic at the Y10-S11 position, were synthesized. According to 1H NMR conformational analyses in aqueous solution and 30% TFE, both PACAP27 and the [S-IBTM10,11]PACAP27 analogue 1 adopt similar ordered structures. PACAP27 shows an N-terminal disordered region (residues H1-F6) and an α-helical conformation within segment T7–L27. For residues S9–R12, our data seem more compatible with a segment of the α-helix than with the β-turn previously proposed for this fragment. In compound 1 the α-helix, also spanning T7–L27 residues, appears slightly distorted at the N-terminus relative to the native peptide. Although this distortion could lead to the marked decrease in binding affinity of this compound at the VIP/PACAP receptors, the lack of the Y10 side chain in analogues 1 and 2 could also significantly affect the binding of these compounds.Work at the Instituto de Quı́mica Médica and Universidad de Navarra was supported by CICYT (SAF 97 0030 and SAF 2000-0147), Fundación La Caixa (97/022) and Comunidad Autónoma de Madrid (08.5/0006/1998). Work at the Instituto de Estructura de la Materia was supported by DGICYT (PB98-0677) and the European Union (CEE B104-97-2086). Work at the Universidad de Barcelona was supported by Generalitat de Catalunya (CERBA). C.M.S. and M.M.-M. are recipients of a pre-doctoral and a post-doctoral fellowship, respectively, from the Comunidad Autónoma de Madrid, Spain. E.de O. is a post-doctoral fellow of Fundació Bosch i Gimpera, Universitat de Barcelona, Spain

Advances in the Development of Non-steroidal Mineralocorticoid-receptor Antagonists

The mineralocorticoid receptor (MR) belongs to the nuclear receptor superfamily and regulates body fluid and electrolyte balance. In the last years, much effort has been put into the development of non-steroidal MR antagonists that overcome the side effects of the marketed steroid drugs, and can be used for the treatment of hypertension and heart failure, among others. Initially, MR was identified in epithelial cells, however it also plays important roles in non-epithelial tissues. In this sense, it is of interest to discover ligands that might induce different MR conformational changes, leading to specific coregulator interactions, which could confer tissue-specific effects. Different series of non-steroidal ligands with diverse central scaffolds has been described, which shows antihypertensive and cardiorenal protective effects. This review covers a description of different non-steroidal MR antagonist families, with special focus on compounds under clinical development. The analysis of the three-dimensional (3D) structures of non-steroidal MR antagonists in complex with the MR ligand-binding domain (LBD), recently reported, highlights the interactions crucial for binding. The structure-activity relationships of known ligands, together with the insights provided by the 3D structures of ligand - LBD MR complexes, could help in the development of non-steroidal MR antagonists with improved properties

Derivados de 1,3-dioxoperhidropirido[1,2-c]pirimidinas como antagonistas de colecistoquinina

Referencia OEPM: P9501857.-- Fecha de solicitud: 26/09/1995.-- Titulares: Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Navarra.Derivados de 1,3-dioxoperhidropirido[1,2-c]pirimidinas como antagonistas de colecistoquinina (ver figura en archivo de texto adjunto). La presente invención se refiere a derivados de 1,3- dioxoperhidropirido [1,2,-c] piriminas, e intermedios para su preparación de fórmula general (I). Dichos derivados son útiles como antagonistas de colecistoquinina (CCK) y por lo tanto como agentes activos sobre el sistema nervioso central y el periférico.Peer reviewe

The TRPM8 antagonist RGM8-51 displays analgesic activity in different pain models

TRPM8 channels are overexpressed in sensory neurons after nerve injury or inflammation, resulting in enhanced sensitivity (allodynia and hyperalgesia) to physical stimulation, and have been implicated in migraine, but the interest of TRPM8 antagonists is still a matter of controversy (1,2). The aim of our work was to evaluate the analgesic activity of a TRPM8 antagonist, RGM8-51, in different pain models, looking for similarities and differences with other antagonists. To this end, we used the mouse oxaliplatin-induced peripheral neuropathy, the chronic constriction injury of the rat sciatic nerve (CCI) and mouse NTG-induced migraine-like models. Compound RGM8- 51 reduces the cold allodynia induced by oxaliplatin, from 15 to 60 min after administration (0.1-1 μg, i.pl.), decreases the nocifensive responses to cold, heat and mechanical stimuli in the CCI model (10 μg, i.pl., 30 mg/Kg, i.p.), and relief chronic pain associated to migraine in mouse, in a sex-dependent manner (10 or 30 mg/Kg, i.v.). The β–lactam derivative RGM8-51 not only has analgesic activity in all assayed animal models, but also seems to have a different mode of interaction with the TRPM8 channel than other antagonists, as suggested by docking studies

Helical peptides from VEGF and Vammin hotspots for modulating the VEGF-VEGFR interaction

The design, synthesis, conformational studies and binding affinity for VEGF receptors of a collection of linear and cyclic peptide analogues of the N-terminal α-helix fragments 13-25 of VEGF and 1-13 of Vammin are described. Linear 13(14)-mer peptides were designed with the help of an AGADIR algorithm and prepared following peptide solid-phase synthetic protocols. Cyclic peptide derivatives were prepared on-resin from linear precursors with conveniently located Glu and Lys residues, by the formation of amide linkages. Conformational analysis, CD and NMR, showed that most synthesized peptides have a clear tendency to be structured as α-helices in solution. Some of the peptides were able to bind a VEGFR-1 receptor with moderate affinity. In addition to the described key residues (Phe17, Tyr21 and Tyr25), Val14 and Val20 seem to be relevant for affinity.Peer Reviewe

The Relationship between Information Utilization and Social Participation among Middle-aged and Older Adults

早大学位記番号:新8355早稲田大

1,3-diphenylpropan-1-ones as allosteric modulators of α7 nACh receptors with analgesic and antioxidant properties

Nicotine acethylcholine receptors (nAChRs) play critical roles in cognitive processes, neuroprotection and inflammation. Results: According to their substituents, 1,3-diphenylpropan-1-one derivatives act as α7 nAChRs negative allosteric modulators (NAM, OMe) or Type I positive allosteric modulators (PAMs, OH). Compounds 7 and 31 were the most effective (989 and 666% enhancement of ACh-induced currents) and potent (EC: 12.9 and 6.85 μM) PAMs. They exhibited strong radical scavenging values. Compound 31, selective over other neuronal nAChR subtypes and with acceptable pharmacokinetic profile, showed antinociceptive effects in a model of inflammatory pain. Conclusion: Compound 31 is a novel, potent and selective α7 nAChR PAM, displaying antioxidant and analgesic activities. The 1,3-diphenylpropan-1-one scaffold could be the base toward more advanced type I PAMs for the treatment of nAChR-mediated diseases.This work was supported by the Spanish MINECO: CSD2008-00005, The Spanish Ion Channel Initiative-CONSOLIDER INGENIO 2010, SAF2011-22802 and BFU2012-39092-C02. The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”. We thank Susana Cámara Garrido for her assistance in the synthesis of some starting compounds and Susana Gerber for technical assistance. BBP thanks the CSIC for a predoctoral fellowship (JAE-Predoc from Junta para la Ampliación de Estudios, co-financed by FSE). Alpha7 nAChRPeer Reviewe

Generation of Molecular Diversity from Amino Acids. A Source for the Discovery of New TRP Channel Modulators

Trabajo presentado en el IV RECI: New Horizons in Ion Channel Research, celebrado en Cuenca (España) del 12 al 13 de febrero de 2013.Ion channels are central and challenging targets in medicinal chemistry but, because of the scarce structural knowledge, rational approaches to ion channel modulators are still rare. Moreover, the multimodal activation of some channels, like TRPs, complicates still more the scenario for rational discovery programs. Due to these facts, most strategies directed to identify ion channel modulators rely on the screening of peptide and small-molecule libraries. In this context, we have been involved in the development of synthetic pathways for the generation of diverse, chiral, highly functionalized linear and heterocyclic scaffolds from amino acids, and in the production of discrete libraries from them. The screening of these libraries on different TRP channels has allowed the discovery of some innovative hits that have progressed to hit-to-lead optimization programs. This communication will deal with the synthesis, structural characterization, and biological evaluation of a collection of β,γ–diaminoester derivatives that display significant activity at TRPV1, TRPM8 and TRPA1 channels. Compound RGM04-7, a selective.Supported by MICINN grants: Consolider-Ingenio 2010 (CSD2008-00005 and CSD2006-00015), SAF2009-09323 and BFU2009-08346, and the Generalitat Valenciana (PROMETEO/2010/046)

Péptidos bloqueantes de termoreceptores y sus usos

La invención se relaciona con péptidos helicoidales capaces de modular la activación de canales termosensoriales y con sus aplicaciones. Más concretamente, la invención se relaciona con péptidos con capacidad de bloquear la activación de los canales TRPV1 y TRPVA por parte de sus ligandos, con composiciones farmacéuticas que comprenden dichos péptidos y con el uso de dichos péptidos y dichas composiciones farmacéuticas para el tratamiento de dolor, inflamación, prurito, enfermedades de las vías respiratorias, enfermedades de la piel, mucosa y/o uñas y desórdenes asociados con desequilibrios del calcio.Peer reviewedUniversidad Miguel Hernández de Elche, Consejo Superior de Investigaciones CientíficasR Informe sobre el estado de la técnica publicado separadament